Abstract
Breast cancer stem cells (BCSCs), which drive tumor progression, recurrence, and metastasis, are considered a major challenge for breast cancer treatments, thus the discovery of novel pathways regulating BCSC maintenance remains essential to develop new strategies to effectively target this population and combat disease mortality. The HGFL-RON signaling is overexpressed in human breast cancers and is associated with increased breast cancer progression, metastasis, and poor prognosis. Here, we report that overexpression of RON/MST1R and HGFL/MST1 in cell lines and primary tumors increases BCSC self-renewal, numbers, and tumorigenic potential after syngeneic transplantation. Transcriptome analyses also reveal that the HGFL-RON signaling pathway regulates additional BCSC functions and supports an immunosuppressive microenvironment to stimulate tumor formation and progression. Moreover, we show that genetic and chemical downregulation of HGFL-RON signaling disrupts BCSC phenotypes and tumor growth by suppressing the RON-mediated phosphorylation/activation of β-CATENIN/CTNNB1 and its effector NF-κB/RELA. These studies indicate that HGFL-RON signaling regulates BCSC phenotypes and the tumor microenvironment to drive tumorigenesis and present HGFL/RON as novel therapeutic targets to effectively eradicate BCSCs in patients.
Highlights
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related deaths among women in the United States, with 29% of women expected to develop invasive breast cancer and 14% of patients expected to die from this disease during 2016 [1]
To examine the importance of hepatocyte growth factor-like protein (HGFL)-dependent RON signaling in Breast Cancer Stem Cells (BCSC), we first investigated the in vivo significance of HGFL-RON signaling in promoting breast cancer growth through regulation of the BCSC population using two distinct and well established murine models of spontaneous breast cancer
Our studies utilizing spontaneous breast cancer models demonstrate that genetic loss of RON and HGFL leads to a decrease in tumor burden which is associated with a reduction in BCSC numbers and their self-renewal ability, suggesting HGFL-RON signaling as an important regulator of the BCSC population
Summary
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related deaths among women in the United States, with 29% of women expected to develop invasive breast cancer and 14% of patients expected to die from this disease during 2016 [1]. While advances in early detection and therapies have decreased breast cancer death rates, 20%–30% of patients develop tumor recurrence and therapeutic resistance, leading to advanced metastatic disease and significant mortality [2,3,4,5]. This highlights the lack of effectiveness of current treatments and the need to understand the underlying mechanisms mediating breast cancer progression to aggressive disease to develop effective treatments to combat disease mortality [6, 7]. The identification of novel molecular pathways supporting BCSC maintenance is critical to develop anticancer drugs targeting BCSCs to effectively combat breast cancer progression and improve the long-term survival of these patients [9, 11, 13, 14]
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